CS233434B1 - 5- [5-phenyl-2-furyl] tetrazol-1-yl-alkanoic acid, their alkali salts and their preparation - Google Patents

Abstract

The invention relates to 5-substituted tetrazol-1-ylalkenoic acids with anti-inflammatory effects, with a further possibility of their use in the preparation of semi-synthetic antibiotics of the beta-lactam type and a method for their preparation. The method for the preparation of the said acids is based on the alkaline hydrolysis of the corresponding acid ethers.

Description

The invention relates to 5-[5-phenyl-2-furyl]tetrazol-1-ylalkanoic acids and slightly alkaline salts with anti-inflammatory effects of general formula 1

(CH ₂ )„- CO ₂ X where X represents hydrogen, sodium, potassium, R represents hydrogen, bromine, chlorine, methyl, methose, trifluoromethyl, a nitro group in the o-, m-, or p- position of the phenyl nucleus and denotes 1,2 and spOsobov their preparation.

These new compounds, not yet described in the literature, are characterized by anti-inflammatory activity, as can be seen from Table 1.

T a b u T k a 1

The antifungal activity of 5-[5-phenyl-2-furyl]tetrezol-1-ylacetic acids of the formula 1, wherein X represents hydrogen, n represents 1 and 8 has the meaning given below.

Compound No. R Dose mg/kg Ferroentual inhibition of inflammation Kaolin Carrageenin edam % edam % Adjuvant edema % 1 25 11 13 19 4-C1 100 ' 21 3 23 2 3-C1 25 50 100 4 0 °n ’n 11 37 ⁺ 23 ⁺ 31 ⁺ 3 25 6 0 19 2-C1 100 2 14 22 4 25 21 0 18 4-Br 100 9 0 10 5 25 6 5 17 3-CF, 100 18 12 32 ⁺ 6 25 14" 0 ⁿ 4 ⁿ 2-CF, 100 14 ^{n about} 12" 7 25 15 ⁿ 13 ⁿ 28* 50 - 22 ⁿ 11 ⁿ H 100 6 ⁿ 19 ⁿ 36 ⁺ 8 25 19 0 0 3-CH, 100 0 8 0 9 25 2 ⁿ 0 ⁿ 5 ⁿ - 4-CH ₃ O 100 18 ⁺ 1$ ^d 7 ⁿ 10 25 19 8 4 2-CH ₃ 100 16 6 21 11 25 12 0 17 2-N0 ₂ 100 0 16 13 Ibuprofen 25 100 . 51 ⁺ 49 ⁺ 50 ⁺ 50 ⁺ 39* 41*

+ ... statistically significant efficacy n ... statistically insignificant efficacy

The compounds according to the invention are prepared by hydrolysis of alkyl esters of 5-[5-phenyl-2-furyl]tetrazol-1-ylalkanoic acids of general formula II

I (CH ₂ ) _n - COjAlk (li) in which Alk represents methyl, ethyl, n-propyl and R an have the same meaning as in formula I. Sodium or potassium hydroxide is used as a hydrolysis agent in an aqueous lower alcohol with a carbon number of 1 to 3, preferably in 50% aqueous ethanol at a temperature of 0 °C to .00 °C, or in alcohol itself with a carbon number of 1 to 3 3 at a temperature of 0 °C to the boiling temperature of the alcohol used, preferably in a 3 M methanolic solution of potassium hydroxide while boiling methanol.

By cooling the reaction mixture, an alkaline salt of the formula t is precipitated, which can be isolated by suction and purified by crystallization from an aqueous solvent. If the corresponding acid of formula 1 needs to be isolated, dilute inorganic acid, e.g. hydrochloric acid or sulfuric acid, is added to the hot solution of the alkaline salt formed by the hydrolysis reaction, and the precipitated acid 1 is isolated by suction and crystallization from a suitable solvent. .

Further, the subject matter of the invention is illustrated by examples without being limited thereto.

Example,

5-[5-(4-Chlorophenyl)-2-furyl]tetrazol-1-ylacetic acid

8.31 g (25 mmol) of ethyl 5-[5-(4-Chlorophenyl)-2-furyl] tetrazol-1-ylacetate is poured into 50 ml of ethanol and a solution of 2.14 g (37.5 mmol) of potassium hydroxide in 50 ml of water. The mixture is heated for 1 h at boiling, then filtered and acidified while hot with 15% hydrochloric acid. The precipitated white crystalline acid is filtered off after cooling. Yield 94%. T. t 23, to 232 °C (ethanol). For C^H^CIN^O^ calculated, or found: 51.24 or 51.34 « C,

2.97 or 3.04% H, 18.38 resp. 18.53 «At 11.63 or 11.43 « Cl.

Example 2

5-[5-(3-Chlorophenyl)-2-furyl]tetrazol-1-ylacetic acid

It was prepared by an analogous procedure as in Example 1 from 8.31 phenyl)-2-furyl]tetrazol-1-yl ethyl acetate. Yield 94 «. T. t. For C^^CIN^O^ calculated, or found: 51.24 or 51.27 « C, 18.38 resp. 18.34 «At 11.63 or 11.80% Cl.

g (25 mmol) 5-[5r(3-chloro249 to 250 °C (ethanol). 2.97 and 2.82 « H, respectively

Example 3

5-[5-(2-Chlorophenyl)-2-furyl]tetrazol-1-ylacetic acid

It was prepared by an analogous procedure as in Example 1 from 8.31 ethyl phenyl)-2-furyl]tetrazol-1-ylacetate. Yield 93 «. M. t. For C^H^CIN^O^ calculated, respectively found: 51.24 resp. 51.34 « C, 18.38 resp. 18.08 «Na 11.63 resp. 11.96 % Cl.

g (25 mmol) 5-[5-(2-chloro)221 to 222 °C (ethanol).

2.97 and 3.02% H, respectively,

Example 4

5-[5-(4-Bromophenyl)-2-furyl]tetrazol-1-ylacetic acid

It was prepared by an analogous procedure as in example 1 from 9.43 g (25 mmol) of ethyl 5-[5-(4-bromophenyl)-2-furyl]tetrazol-1-yl ethane. Yield 94%. M.p. 243 to 245 °C. For C^HgBrN^O^ calculated, or found: 44.72 or 44.98% C, 2.59 resp. 2.80% H, 16.04 resp. 16.09% N and 22.88 resp. 22.98 » Bro.

Example 5

5-[5-Phenyl-2-furyl] tetrazol-1-ylacetic acid

It was prepared by an analogous procedure as in Example 1 from 7.46 g (25 mmol) of ethyl 5-[5-(phenyl)-2-furyl] tetrazol-1-yl acetate. Yield 9.%. M.p. 227 to 229 °C (ethanol). For calculated or found: 57.77 or 57.58% C, 3.72 or 3.80% H, 20.73 resp. 20.71% N.

Example 6

5-[5-(4-Methylphenyl)-2-furyl]tetrazol-1-ylacetic acid

It was prepared by an analogous procedure as in Example 1 from 7.8 g (25 mmol) of ethyl 5-(4-methylphenyl)-2-furyl]tetrazol-1-ylacetate. Yield 95%. M.p. 2.9 to 221 °C (ethanol).

For calculated or found: 59.15 or 58.95% C, 4.25 or 4.44% H and 19.70 resp. 19.36% N.

Example 7

5-[5-(4-Methoxyphenyl)-2-fury]tetrazol-1-ylacetic acid

It was prepared by an analogous procedure as in Example 1 from 8.20 g (25 mmol). Ethyl 5-[5-(4-methoxyphenyl)-2-furyl]tetrazol-1-ylacetate. Yield 93%. M.p. 223 to 224 °C (ethanol). For calculated or found: 56.00 or 56.06% C, 4.02 or 4.06% H and 18.65 resp. 18.81% N.

Example

5-[5-(4-Nitrophenyl)-2-furyl] tetrazol-1-ylacetic acid

It was prepared by an analogous procedure as in Example 1 from 8.58 g (25 mmol) of ethyl 5-[5-(4-nitrophenyl)-2-furyl]tetrazol-1-yl ethane. Yield 89%. M.p. 214 to 216 °C (ethanol).

For calculated or found: 49.53 or 49.70% C, 2.87 or 2.91% H and 22.21 resp. 22.23%N.

Example 9

5-[5-(3-Trifluoromethylphenyl)-2-furyl]tetrazol-1-ylacetic acid

9.15 g (25 mmol) of ethyl 5-[5-(3-Trifluoromethylphenyl)-2-furyl]tetrazol-1-ylacetate was dissolved in 100 ml of hot methanol and 10 ml of a 3M methanolic potassium hydroxide solution was added to it. The reaction mixture with the excluded potassium salt is stirred for 1 h at 60 °C, then it is concentrated to a third volume, the residue is dissolved by adding 50 ml of hot water and the filtered clear solution is acidified with 15% hydrochloric acid to pH 1. The white crystalline acid that is excluded is filtered off after cooling. Yield 92%. M.p. 231 to 233 °C (ethanol). For C^HgF^B^O-j calculated, or found: 49.71 or 49.82% C, 2.68 or 2.60% H and 16.56 resp. 16.64% N/

Example

5-[5-(3-Methylphenyl)-2-furyl]tetrazol-1-ylacetic acid

It was prepared by an analogous procedure as in Example 9 from 7.8 g (25 mmol) of ethyl S-1jj-O-methylphenyl)-2-furyl]tetrazol-1-ylacetate. Yield 92%. M.p. 270 to 271 °C (ethanol).

Calculated and found: 59.15 and 58.96% C, 4.25 and 4.38% H, and 19.70 and 19.70% N, respectively.

They applied

5-[5-(2-Nitrophenyl)-2-furyl]tetrazol-1-ylacetic acid

It was prepared by an analogous procedure as in Example 9 from 8.58 g (25 mmol) of ethyl 5-[5-(2-nitrophenyl)-2-furyl]tetrazol-1-yl acetate. Yield 89 «. T. m. 214 to 216 °C (ethanol).. For Oj calculated or not found: 49.53 or 50.14 « C, 2.87 resp. '2.90 « H and 22.21 respectively. 22.30% N. ’ “

Example 12

5-[5-(2-Trifluoromethylphenyl)-2-furyl]tetrazol-1-ylacetic acid

9.15 g (25 mmol) of ethyl 5-[5-(2-Trifluoromethylphenyl)-2-furyl]tetrazol-1-ylacetate is poured into 50 ml of methanol and a solution of 1.5 g (37.5 mmol) of sodium hydroxide in 50 ml of water. The mixture is heated to boiling for 1 h, then filtered and acidified while hot with 15% hydrochloric acid. The cured white acid is filtered off after cooling. Yield 92 «. M.p. 213 to 215 °C (ethanol). For C^HgFjN^Oj calculated, or found: 49.71 or 49.97% C,

2.68 or 2.56 «Ha 16.56 or 16.63 « N.

Example 13

5-[5-(2-Methoxyphenyl)-2-furyl] tetrazol-1-ylacetic acid

It was prepared by an analogous procedure as in Example 12 from 8.20 g (25 mmol) of ethyl 5-[5-(2-methoxyphenyl)-2-furyl]tetrazol-1-yl acetate. Yield 92 «. M.p. 258 to 259 °C (ethanol) For C..H. _? N,0, calculated or found: 56.00 or 56.02% C, 4.02 or 4.12 « Ha 18.65 or 18.70 « N.

Example 14

5-[5-(3-Chlorophenyl)-2-furyl]tetrazol-1-ylpropionic acid

It was prepared by an analogous procedure as in Example 1 from 8.66 g (25 mmol) of ethyl 5-(5-(3-chlorophenyl)-2-furyl]tetrazol-1-ylpropionate. Yield 89 «. M.p. 247 to 248 °C (ethanol). For C ₁₍ |H^ ^CIN^O^ calculated or found: 52.76 or 52.56 « C, 3.47 or

3.55 « H, 17.57 or 17.56 «At 11.12 or 11.22 « Cl.

Example 15

Potassium 5-[5-(4-Chlorophenyl)-2-furyltetrazol-1-yloctane

8.31 g (25 mmol) of ethyl 5-[5-(4-Chlorophenyl)-2-furyl] tetrazol-1-yloctane is poured into 50 ml of ethanol and a solution of 2.14 g (37.5 mmol) of potassium hydroxide in 50 ml of water. The mixture is heated for 1 h at boiling point, then filtered and allowed to cool. The crystallized potassium salt is filtered off and washed with 75% aqueous ethanol. Yield 54 «. M.p. 338 to 340 °C (ethanol-water). For C^HgClKN^O^ calculated, or found: 45.55 or 45.29 « C, 2.35 or 2.30 « H, 16.34 or 16.36 «On 10.34 or 10.56 « Cl.

Example 16

Potassium 5-[5-(3-Chlorophenyl)-2-furyl]tetrazol-1-yloctane

It was prepared by an analogous procedure as in Example 15 from 8.31 g (25 mmol) of ethyl 5-[5-(3-Chlorophenyl)-2-furyl]tetrazol-1-ylacetate. Yield 56 56. M.p. 335 to 338 °C (ethanol-water). For C^HgClKN^O^ calculated, or found: 45.55 or 45.54% C, 2.35 or

2.61% H, 16.34 resp. 16.54% N and 10.34 resp. 10.70% Cl.

Example 17

Potassium 5-[5-(2-Chlorophenyl)-2-furyl] tetrazol-1-ylloothane

It was prepared by an analogous procedure as in Example 15 from 8.31 g (25 mmol) of ethyl 5-[5-(2-chlorophenyl)-2-furyl]tetrazol-1-ylacetate. Yield 55 36. M.p. 328 to 330 °C (ethanol-water). For C^HgClKN^Oj calculated, or found: 45.55 or 45.58% C, 2.35 resp.

2.40% H, 16.34 resp. 16.44 56 N and 10.34 respectively. 10.87 56 Cl.

Example 18

Potassium 5-[5-(4-Bromophenyl)-2-furyl]tetrazol-1-yloctane

It was prepared by an analogous procedure as in Example 15 and 9.43 g (25 mmol) of ethyl 5-[5-(4-bromophenyl)-2-furyl]tetrazol-1-ylacetate. Yield 61 56. M.p. 336 to 338 °C (ethanol-water). For C^HgBrKN^O^ calculated, or found: 40.32 or 40.24 56 C, 2.08 or 2.00 56 H, 14.46 or 14.50 56 N and 20.63 respectively. 21.02 * Bro.

Example 19

Potassium 5-[5 ^J Phenyl-2-furyl] tetrazol-1-ylacetate

It was prepared by a procedure analogous to that of Example 15 and 7.46 g (25 mmol) of ethyl 5-[5-(phenyl)-2-furyl]tetrazol-1-ylacetate. Yield 58 56. M.p. 331-334 °C (ethanol-water).

For C^HgKN^O^ calculated, or found: 50.63 rasp. 50.77 56 C, 2.94 or 2.93 56H,

18.17 and 17.90 56 N respectively.

Example 20

Potassium 5-[5-(4-Methylphenyl)-2-furyl]tetrazol-1-ylacetate

It was prepared by an analogous procedure as in Example 15 and 7.80 g (25 mmol) of ethyl 5-[5-(4-methylphenyl)-2-furyl]tetrazol-,-ylacetate, Yield 58 56. ΐ. th. 337 to 339 °C (ethanol-water).

Example 21

Potassium 5-[5-(4-Methoxyphenyl)-2-furyl]tetrazol-1-yloctane

It was prepared by an analogous procedure as in Example 15 from 6.20 g (25 mmol) of ethyl 5-[5-(4-methoxyphenyl)-2-furyl]tetrazol-1-yl ethane. Yield 60 56. M.p. 326 to 328 °C (ethanol-water). For C^HjjKN^O^ calculated, or found: 49.69 or 49.60 56 C, 3.27 or

3.32 56 H and 16.55 respectively. 16.61 56N.

7.

ř r í k 1 β J 22

Potassium 5-[5-(4-Nitrophenyl)-2-furyl]tetrazol-1-yloctane

It was prepared by an analogous procedure as in Example 15 from 8.58 g (25 amol) of ethyl 5-[5-(4-nitrophenyl)-2-fury]tetrazol-1-ylacetate. Yield 51%. 1. mp 290 to 291 °0 (ethanol-water). For C^HgKN^O^ calculated, or found: 44.19 or 44.03 « C, 2.28 resp. 2.3ί % H and 19.82 resp. 19.71 « N.

Example 23

Potassium 5-[5-(3-Trifluoromethylphenyl)-2-fury2]tetrazol-1-yloctane

9.15 g (25 mmol) of ethyl 5-[5-(3-Trifluoromethylphenyl)-2-furyl] tetrazol-1-ylacetate was dissolved in 100 ml of hot methanol and 10 ml of a 3M methanolic potassium hydroxide solution was added to it. The reaction mixture with the cured potassium salt is stirred for 1 h at 60 °C, then cooled, the potassium salt! is filtered off and washed with 75% aqueous ethanol, Extract 69 «. M.p. 336 to 338 °C (ethanol-water). For C ₁ ^ΗθΚΡ^Ν^Ο^ calculated, or found: 44.68 or

44.74 « C, 2.14 or 2.18 «Ha 14.88 or 14.67% N.

Example 24

Potassium 5-[5-(3-Methylphenyl)-2-furyl]tetrazol-1-ylacetate

It was prepared by a procedure analogous to that in Example 23 from 7.80 g (25 mmol) of ethyl 5-[5-(3-methylphenyl)-2-furyl]tetrazol-1-ylacetate. Yield 70%. M.p. 332 to 333 °C (ethanol-water). For C^H^KM^O^ calculated or found: 52.16 or 51.90% C, 3.43 or 5

3.52 «Ha 17.37 or 17.40 « N.

Example 25

Potassium 5-[5-(2-Nitrophenyl)-2-furyl]tetrazol-1-yloctane

It was prepared by an analogous procedure as in Example 23 from 8.58 g (25 mmol) of ethyl 5-[5-(2-nitrophenyl)-2-furyl]tetrazol-1-yl acetate. Extract 66 «. M.p. 290 to 292 ^B C (ethanol-water). For C^HgKN^Og calculated, or found: 44.19 or 44.25 « C, 2.28 resp. 2.31 «Ha 19.82 or 19.71 « N.

Claims (29)

1. 5- [5-Phenyl-2-furyl] tetrazol-1-ylalkanoic acids and their alkali salts with anti-inflammatory effects of the general formula I ^R. (ch ₂ ) "- co ₂ x (I) where X is hydrogen, sodium, potassium, R is hydrogen, bromo, chloro, methyl, methoxy, trifluoromethyl, nitro in the o-, m-, or p-position of the phenyl ring, n is 1,2. 2. 5- [5- (4-Chloro-phenyl) -2-furyl] -tetrazol-1-yl-acetic acid 3. 5- [5- (3-Chloro-phenyl) -2-furyl] -tetrazol-1-yloic acid 4. 5- [5- (2-Chloro-phenyl) -2-furyl] -tetrazol-1-ylacetic acid 5. 5- [5- (4-Bromo-phenyl) -2-furyl] -tetrazol-1-yloic acid 6. 5- (5-Phenyl-2-furyl) -tetrazol-1-yloic acid 7. 5- [5- (4-Methylphenyl) -2-furyl] tetrazol-1-ylacetic acid 8. 5- [5- (4-Methoxyphenyl) -2-furyl] tetrazol-1-ylacetic acid 9. 5- [5- (4-Nitrophanyl) -2-furyl] tetrazol-1-ylacetic acid 10. 5- [5-C3-Trifluoromethyl-phenyl) -2-furyl] -tetrazol-1-yloic acid 11. 5- [5- (3-Methyl-phenyl) -2-furyl-tetrazol-1-yloic acid 12. 5- [5- (2-Trifluoro-ethyl-phenyl) -2-furyl] -tetrazol-1-yloic acid 13. 5- [5- (2-Nitrophenyl) -2-furyl] tetrazol-1-ylacetic acid Ί4. 5 - [, 5- (2-Methoxyphenyl) -2-furyl] tetrazol-1-yloic acid 15. 5- [5- (3-Chloro-phenyl) -2-furyl] -tetrezol-1-yl-propionic acid 16. Potassium 5- [5- (4-Chlorophenyl) -2-furyl] tetrazol-1-yl acetate 17. Potassium 5- [5- (3-Chlorophenyl) -2-furyl] tetrazol-1-yl acetate 18. Potassium 5- [5- (2-Chloro-phenyl) -2-furyl] -tetrazol-1-yl-acetate 19. Potassium 5- [5- (4-Bromo-phenyl) -2-furyl] -tetrazol-1-yl-acetate 20. Potassium 5- [5- (phenyl) -2-furyl] tetrazol-1-yl-acetate 21. Potassium 5- [5- (4-methylphenyl) -2-furyl] tetrazol-1-yl acetate 22. Potassium 5- [5- (4-methoxyphenyl) -2-furyl] tetrazol-1-yl acetate 23. Potassium 5- [5- (4-nitrophenyl) -2-furyl] tetrazol-1-yl acetate 24. Potassium 5- [5- (3-trifluoromethylphenyl) -2-furyl] tetrazol-1-yl acetate 25. Potassium 5- {5- (3-methylphenyl) -2-furyl] tetrazol-1-yl acetate 26. Potassium 5- [5- (2-nitrophenyl) -2-furyl] tetrazol-1-yl acetate 27th Sp6sob preparation of compounds of formula I according to one roll, characterized in that the alkyl esters of 5- [5-phenyl-2-furyl] tetrazol-1-ylalkanových acid of formula II (II) (CH _{2) n} - wherein COjAlk Alk represents methyl, ethyl, n-propyl, and Wounds have the same meaning as in formula I, hydrolyzed by treatment with alkali hydroxides in an aqueous-alcoholic or only alcoholic medium to isolate the alkali salt, or optionally acidify the alkali salt with an inorganic acid. 28. The method of claim 27, wherein the alkali hydroxide is sodium hydroxide, or preferably potassium hydroxide. 29. A method according to claim 27, wherein the alcoholic and the alcoholic strengths of the composition are as follows. the aqueous-alcoholic medium will use methanol, ethanol, n-propanol, 2-propanol, preferably ethanol. 30. A method according to claim 27, wherein the hydrolysis is carried out at a temperature of 0 ° C to 100 ° C and 0 ° C to the boiling point of the alcohol used.